Submitting risk management plans guidance document: When to provide an RMP

On this page

• Risk management plan policies
• With a drug submission or application
• Post-market RMP submissions
• Risk management plan updates

Risk management plan policies

Sponsors/MAHs are to submit a risk management plan (RMP) to Health Canada if:

• there is a significant degree of uncertainty about the risks associated with the drug or
• the drug presents a serious risk of injury to human health that warrants measures, other than labelling, to reduce the probability or severity of such an injury

You should submit an RMP for the following scenarios:

• when expected as part of a new drug submission (NDS), abbreviated new drug submission (ANDS) or abbreviated extraordinary use new drug submission (AEUNDS)
• when Health Canada requests one following an application seeking a drug identification number (DIN)
• with any extraordinary use new drug submission (EUNDS)
• if a supplement to a submission results in the need for a new RMP or an update to an RMP to assess the safety and effectiveness of the drug
• when Health Canada requests one post-authorization
• when you have determined that an update is necessary due to significant differences in risks or uncertainties
• the measures that you intend to take are significantly different from those in the existing plan

We have provided some further explanations and examples of when to file an RMP with us.

With a drug submission or application

An RMP helps the Minister assess the safety and effectiveness of the drug as part of drug submissions.

You are expected to evaluate and determine if you require an RMP for your product.

You are expected to file an RMP with your drug submission or application for:

• new drug submissions that include new active substances (NAS)
• generic and biosimilar drugs whose reference product has an RMP with additional pharmacovigilance measures or additional risk minimization measures
• combinations or co-packages of products where at least 1 of the components is a drug that has its own DIN with an RMP that includes additional pharmacovigilance measures or additional risk minimization measures
• a drug that is the subject of an “extraordinary use” new drug submission

We may also request in writing an RMP after you submit an application for a DIN or a submission for a notice of compliance (NOC) where:

• there is a significant degree of uncertainty about the risks associated with the drug or
• the drug presents a serious risk of injury to human health that warrants measures, other than labelling, to reduce the probability or severity of such an injury

We may consider that there is a significant degree of uncertainty about the risks associated with a drug when:

• the data we reviewed is not enough to resolve uncertainties about a drug’s safety and effectiveness, for example:
  • missing information for anticipated uses, such as long-term use or in particular populations
  • risks not well characterized prior to the drug submission or application
• the anticipated use of the drug includes settings that differ from clinical trials, such as:
  • in a larger population
  • a population with additional or different risk factors, compared to the studied population
• the significance of uncertainty may vary between drug categories
  • for example, vaccines are given to large, generally healthy populations, where benefit-risk calculation may differ from that of some therapeutic drugs
    • for that reason, RMPs may be requested for some vaccines that do not contain new active substances
• there are potential risks associated with the drug, but more information is needed to monitor and characterize those risks and their impact on the drug’s safety and effectiveness
  • examples of risks or uncertainties that may not be well characterized could include the potential for off-label use, long-term use or use in patients with comorbidities

We may also consider that there is a significant degree of uncertainty about the risks associated with a drug in the following scenarios:

• a product produced by innovative technologies may merit greater scrutiny than one made by using established, well-characterized ones
  • examples could include certain cell or gene therapies
• new information contained in a supplement to a submission introduces a significant degree of uncertainty about the drug’s safety and where further monitoring and characterization may be needed due to:
  • a change in the recommended route of administration, dosage or dosage form
  • changes in the indication, such as the extension of an existing indication to a wider population or populations with unique health and safety needs
  • new conditions of use, ranging from administration by a health care provider to self-administration in the home

Due to the uncertainty surrounding these risks, an RMP may be requested to further study, characterize and manage the risks.

Health Canada may consider that the drug presents a serious risk of injury to human health that warrants measures, other than labelling, to reduce the probability or severity of such an injury when:

• a serious risk has been identified and characterized and where additional pharmacovigilance measures or additional risk minimization measures or interventions may be needed, to prevent or minimize the risk or for the benefits of the product to outweigh its risks
  • examples could include relevant risks identified from reports of adverse reactions in clinical trials, epidemiological studies and real-world evidence, including issues emerging from real-world use (off-label use, medication errors)
• the drug is a member of a class of drugs with known safety concerns or uncertainties for which additional pharmacovigilance measures or additional risk minimization measures may be in place
  • additional risk minimization measures could include physician or patient educational materials, controlled access or distribution
• a drug previously associated with actions such as cancelling a DIN or discontinuing its sale due to a serious safety issue or significant uncertainty
• for an authorized product with or without an RMP for which a supplement to a submission is submitted to support a significant change to a label’s safety information, such as to add:
  • information on the characteristics of a risk
  • new recommendation for risk mitigation, such as testing and monitoring
  • new information stemming from a pharmacovigilance activity
• for an authorized product with or without an RMP for which a supplement to a submission is submitted to support a significant change to the packaging that could lead to dosing or medication errors, such as:
  • a change in packaging

For a discussion of "serious risk", consult:

• annex A of the Guide to authorities under the Protecting Canadians from Unsafe Drugs Act (Vanessa’s Law)

If you have questions about submitting an RMP to Health Canada, contact the Regulatory Project Management Office, Marketed Health Products Directorate early on in the application process.

Pre-submission meetings

Before filing a submission or application, you can request a pre-submission meeting to discuss all aspects of your submission, including RMPs.

For help:

• refer to the Guidance document: Management of drug submissions and applications for instructions on how to request pre-submission meetings
• request a pre-submission meeting, if needed, and indicate in the request that you wish to discuss items related to the RMP, if applicable

During a pre-submission meeting, MHPD representatives will provide appropriate guidance on the content and format of the RMP, based on the information provided in the meeting package. You may:

• include a draft RMP in the data package for a pre-submission meeting or
• provide an outline of the RMP or any potential questions about the RMP

An RMP that is requested as part of the submission or application should be included with the submission package. You are encouraged to include a rationale if you consider that an RMP is not needed as part of the submission.

Generic and biosimilar drugs

You should file an RMP with the submission or application for a generic or biosimilar drug whose reference product has an RMP with additional pharmacovigilance measures or additional risk minimization measures, such as:

• registries
• controlled access or distribution
• post-market safety or utilization studies
• distribution of educational materials for patients or health care providers

Sponsors/MAHs of a generic or biosimilar drug should:

• compare the risk profile of their drug to the reference product and
• consider additional pharmacovigilance measures or additional risk minimization measures accordingly

Health Canada may also request an RMP for generic or biosimilar drugs when there are unique safety issues associated with the drug.

We encourage you to review the information available for the reference product in the Drug Product Database or the Canadian Product Monograph, before you submit your drug submission or application. This will help you determine whether the reference product has additional pharmacovigilance measures or additional risk minimization measures. For reference products with additional measures, if an RMP summary is available, Health Canada will provide it upon request.

As part of your RMP, you are expected to consider the need for similar additional pharmacovigilance measures or additional risk minimization measures for the drug. Provide a description of the measures if appropriate. If the additional measures for your generic or biosimilar RMP differ from the reference product RMP, provide a rationale.

If you have questions about submitting an RMP to Health Canada, contact the Regulatory Project Management Office, Marketed Health Products Directorate early on in the application process.

Administrative submissions

For submissions that meet the criteria for administrative processing, post-market requirements, including RMP elements, are expected to continue as per previous authorization.

For more information, consult:

• Guidance document: Administrative processing of submissions and applications involving human or disinfectant drugs

Post-market RMP submissions

Health Canada may also request an RMP for a drug for which a DIN has been assigned when no RMP has been submitted to us before.

We will make our decision on a product-by-product basis, depending on information available at the time. Our request may be part of an ongoing review to support informed regulatory decision-making about the drug, including decisions about its safety and effectiveness.

We may request an RMP for a drug that has already been assigned a DIN, when there is a significant degree of uncertainty about the risks associated with the drug. For example:

• a drug is associated with actions subsequent to authorization, such as suspension of a NOC or stop sale, especially if the action was linked to a serious safety issue or significant uncertainty
• an emerging serious safety issue of significant potential risk is confirmed from a signal assessment that requires further characterization to identify how the risk will impact the drug’s safety and effectiveness
• a major new safety concern is found in a product from the same class or there is evidence of an off-label use for which the risks are potentially serious but poorly characterized

We may also request an RMP for drugs that have already been assigned a DIN, when the drug presents a serious risk of injury to human health that warrants measures, other than labelling, to reduce the probability or severity of such an injury. For example:

• an emergent serious risk has been identified and additional pharmacovigilance measures or additional risk minimization measures may be needed to prevent or minimize the risk
• a safety signal or significant change identified in what is known about the risks of the drug

You should provide the RMP within the timeframe specified in the request. You may request an extension for our consideration, along with a rationale for the request, if needed.

Risk management plan updates

You should submit an update to the RMP for a drug for which a DIN has been assigned if the currently known risks associated with the drug, or uncertainties about those risks, are significantly different from those described in the existing RMP. This is because the existing RMP may no longer fulfill its purpose, which is to identify and characterize the risks associated with the drug and prevent or reduce those risks or address uncertainties.

RMP updates should be submitted as soon as feasible.

Examples of risks and uncertainties that are significantly different:

• new or heightened risk or uncertainty
  • new emerging or serious post-market safety issue is identified
  • new relevant serious safety risk is identified for a similar product in the class
  • new or increased risk from medication error, accidental exposure or off-label use
• new or expanded target population, for example, as a result of a new indication
• new information in the form of a safety signal or important potential risk information
• new evidence (qualitative or quantitative) about risks or uncertainties as a result of risk-monitoring or risk-characterization activities
• change to the safety specification when another regulator has approved the addition, removal or reclassification of a safety concern

Risks and uncertainties may be identified from a number of sources, such as:

• final study results that confirm a safety risk
• an annual summary report under section C.01.018 of the Food and Drug Regulations(FDR)
• an assessment ordered under section 21.31 of the Food and Drugs Act (FDA)
• an issue-related summary report under section C.01.019 of the FDR
• a foreign regulatory action (for example, reported under section C.01.050 of the FDR)
• filing of a supplement to a submission under section C.08.003 of the FDR

You should also submit an RMP update when the measures that you intend to take to address and monitor the uncertainties about a drug's risks, or to prevent or reduce those risks, differ significantly from those described in the existing plan. For example:

• new additional pharmacovigilance measures or new additional risk minimization measures are added
• additional pharmacovigilance measures or additional risk minimization measures are removed
• additional pharmacovigilance measures or additional risk minimization measures are significantly altered
• evaluation of the effectiveness of the additional risk minimization measures has changed
• elements of study protocols (objectives, population or due date of final results) for any of the studies requested by Health Canada and listed in the existing RMP or the Canadian-specific addendum have changed
• measures included in the existing RMP to identify and characterize risks associated with the drug and to prevent or reduce those risks or address uncertainties are no longer sufficient

You should also submit an RMP update if a change to a risk minimization tool (RMT) would have a significant impact on the success or objective of the additional measure.

The following changes are not considered significant:

• changes made to the RMP that are not related to the conditions of use outlined in the Canadian product monograph, or the risks, uncertainties or additional pharmacovigilance measures or additional risk minimization measures described in the existing RMP
• administrative changes, including routine maintenance or structure, layout or format changes to RMTs, unless these have an impact on the:
  • implementation of the measures contained in the RMP
  • content of the RMP summary, when one is included in the existing plan

However, you should assess if changes made to an RMP in a foreign jurisdiction or to the reference RMP are relevant to:

• the safety specification
• additional pharmacovigilance measures or
• additional risk minimization measures

You should assess if the following are sufficient:

• detailed description of the risks in the RMP
• pharmacovigilance plan to address and monitor the uncertainties about risks associated with the drug
• risk minimization measures to prevent or reduce the risks associated with the drug

You should provide an updated RMP if your assessment shows a significant difference to the safety specification or to the additional pharmacovigilance measures or additional risk minimization measures.

For generic and biosimilar products, you should review available information on the reference product to determine if significant updates have been made to the RMP for that reference product. If this is the case, you may need to submit an updated generic or biosimilar product RMP.

If the Canadian reference product has been discontinued, you are encouraged to review relevant available information and to monitor developments that could impact your RMP, when available.

Products with dormant DINs may still meet the threshold that would warrant an update to an RMP. Until products have been discontinued, the RMP update principles continue to apply.

If you have questions about submitting an RMP to Health Canada, contact the Regulatory Project Management Office, Marketed Health Products Directorate early on in the application process.

Updates requested by the Minister

Health Canada may request an updated RMP when the Minister has reasonable grounds to believe that the:

• risks associated with the drug or the uncertainties relating to them are significantly different than those that are described in the existing RMP
• drug presents a serious risk of injury to human health that warrants that measures that are significantly different than those described in the existing RMP be taken to reduce the probability or severity of such an injury

Examples of measures to reduce the probability or severity of a serious injury:

• risk communications
• patient or health care professional education
• patient testing and monitoring
• controlled access or distribution
• pregnancy prevention programs

Generally, the Minister would request such updates to an RMP when the existing RMP is no longer sufficient to:

• identify and characterize the risks associated with the drug and to prevent or reduce those risks or address uncertainties or
• assess the drug’s safety and effectiveness

You should provide the RMP update within the timeframe specified in the request. You may request an extension for our consideration, along with a rationale for the request, if needed.